SUMMARY Mycobacterium avium (MAC) and other non-tuberculous mycobacteria (NTM) can cause chronic, insidious and often debilitating lung disease necessitating complicated and extensive multi-drug antibiotic therapy that can be life-long. Additionally, 50% of treated patients who have culture conversion to negative will suffer a relapse of either their existing infection or a new infection. While NTM are ubiquitous in the environment and human exposure throughout life is frequent, pulmonary disease is found almost exclusively among the elderly. It is therefore not surprising that pulmonary NTM disease is increasing in incidence and prevalence, mirroring changes in the overall age structure of the U.S. Mechanisms underlying the increased susceptibility to NTM disease with age are not well understood. Consequently, there is an unmet need in virtually all aspects of this disease and its management, including an understanding of disease pathogenesis. Adding urgency to this research area is the fact that the U.S. Census Bureau estimates that by 2030, more than 20% of the US residents are projected to be at least 65 years old and over. In this application, we propose to test the central hypothesis that aged individuals are more susceptible to NTM disease due to defects in Th1 T cell immunity coupled with dysregulation in lung microbiome that favor the acquisition of pathogenic bacteria. To that end, we will leverage the highly translational rhesus macaque model to first identify age-associated changes in immunological parameters, inflammatory markers and microbial community. Then, we will leverage a novel rhesus macaque model established by our group that recapitulates the hallmarks of pulmonary MAC disease to carry out experimental prospective studies to uncover age-mediated alterations in immune responses and lung microbial communities that are associated with susceptibility to and development of chronic NTM pulmonary disease. These studies will lead to novel insight into the pathogenesis of this chronic lung disease that causes significant morbidity in the elderly and continues to increase in incidence and prevalence as the American population ages. Identification of immune or microbiome correlates of protection or risk of disease could lead directly to improvements in the clinical care of these patients and the prevention of this disease in the elderly.